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Cardiac risk factors and prevention
Original research
Leisure-time and occupational physical activity and health outcomes in cardiovascular disease
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  1. Nadia E Bonekamp1,
  2. Frank L J Visseren1,
  3. Ynte Ruigrok2,
  4. Maarten J M Cramer3,
  5. Gert Jan de Borst4,
  6. Anne M May5,
  7. Charlotte Koopal1
  8. on behalf of the UCC-SMART Study group
    1. 1 Department of Vascular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
    2. 2 University Medical Center Utrecht Brain Center, Department of Neurology and Neurosurgery, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
    3. 3 Department of Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
    4. 4 Department of Vascular Surgery, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
    5. 5 Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
    1. Correspondence to Dr Frank L J Visseren, Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, PO Box 85500, 3508 GA, The Netherlands; F.L.J.Visseren{at}umcutrecht.nl

    Abstract

    Objective In healthy populations, leisure-time physical activity (LTPA) improves health outcomes, while, paradoxically, occupational physical activity (OPA) is associated with detrimental health effects. This study aimed to investigate the associations of LTPA and OPA with mortality, cardiovascular events and type 2 diabetes (T2D) in patients with cardiovascular disease (CVD).

    Methods In 7058 outpatients with CVD (age 61±10 years, 75% male) from the prospective Utrecht Cardiovascular Cohort-Second Manifestations of ARTerial disease cohort, Cox models were used to quantify the associations between self-reported LTPA and OPA and all-cause mortality, cardiovascular events and T2D.

    Results Over 8.6 years (IQR: 4.6–12.5) of follow-up, 1088 vascular events, 1254 deaths and 447 incident T2D cases occurred. The top LTPA quarter had a lower risk of all-cause mortality (HR 0.63, 95% CI 0.54 to 0.74), recurrent cardiovascular events (HR 0.72, 95% CI 0.60 to 0.84) and incident T2D (HR 0.71, 95% CI 0.55 to 0.93), compared with the lowest quarter. The continuous LTPA associations were reverse J-shaped for all-cause mortality and vascular events and linear for T2D. OPA (heavy manual vs sedentary) showed a trend towards an increased risk of all-cause mortality (HR 1.08, 95% CI 0.86 to 1.35), cardiovascular events (HR 1.15, 95% CI 0.91 to 1.45) and T2D (HR 1.04, 95% CI 0.72 to 1.50). The detrimental effects of higher OPA were more pronounced in men, never-smokers, people with higher education and active employment.

    Conclusions In patients with CVD, LTPA was associated with lower risk of all-cause mortality, recurrent cardiovascular events and incident T2D. In contrast, OPA seemed to increase the risk of these outcomes. These findings support the existence of a physical activity paradox in patients with CVD.

    • diabetes mellitus
    • epidemiology
    • stroke
    • coronary artery disease
    • peripheral vascular diseases

    Data availability statement

    Data are available upon reasonable request. The data that support the findings of this study are available from the corresponding author upon reasonable request.

    https://doi.org/10.1136/heartjnl-2022-321474

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      WHAT IS ALREADY KNOWN ON THIS TOPIC

      • In apparently healthy populations, leisure-time physical activity and occupational physical activity have opposite health effects: while leisure-time physical activity is associated with reduced risk of all-cause mortality and cardiovascular events, occupational physical activity increases these risks. This physical activity paradox may be more pronounced in patients with cardiovascular disease, due to pathophysiological changes after cardiovascular events.

      WHAT THIS STUDY ADDS

      • This study shows that leisure-time physical activity has a strong protective association with all-cause mortality (HR 0.63, 95% CI 0.54 to 0.74), cardiovascular events (HR 0.72, 95% CI 0.60 to 0.84) and type 2 diabetes risk (HR 0.71, 95% CI 0.55 to 0.93) in patients with cardiovascular disease, while physical activity at work might be associated with unfavourable health effects in this population (HRs around 1.10 with 95% CI including 1.00, for the three outcomes).

      HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

      • This study shows that physical activity at work does not provide similar health benefits as leisure-time physical activity and may even have harmful effects for patients with cardiovascular disease. For clinical practice, our results indicate that physical activity at work should not be regarded as a substitute for physical activity in leisure time.

      Introduction

      Physical activity has extensively been shown to reduce the risk of cardiovascular disease (CVD) in apparently healthy individuals1 and is a key recommendation in guidelines for CVD prevention and treatment.2 3 Physical activity’s benefits result from reducing inflammation and improving cardiorespiratory fitness4 5 as well as attenuation of traditional cardiovascular risk factors such as systolic blood pressure and lipid profile.6 7

      Physical activity can be categorised into occupational physical activity (OPA), comprising all work-related activities, and leisure-time physical activity (LTPA), comprising all activities outside the workspace, such as sport and transport-related activities like walking. In apparently healthy populations, higher LTPA confers relative risk reductions for all-cause mortality (up to 35%),8 CVD (up to 55%)9 and type 2 diabetes (T2D) (up to 30%).9 10 In contrast, increased OPA does not unequivocally show such benefits, with some studies even indicating that more physically demanding OPA increases CVD risk, especially in men.11–14 This contradiction in the effects of LTPA and OPA has been called the physical activity paradox.12

      LTPA and OPA may affect patients with CVD differently than patients from the general population. LTPA is commonly regarded as beneficial for atherosclerotic plaque stability, but OPA has been associated with an increased rate of plaque progression.15 16 Evidence from subgroup analyses of observational studies indicates that LTPA reduces CVD and all-cause mortality risk in patients with a history of CVD.17 18 On the other hand, CVD subgroups in observational studies on OPA show that physically demanding OPA might be associated with an increased risk of cardiovascular events and mortality and even show that higher LTPA could have a detrimental effect in patients with CVD with physically demanding OPA.16

      In this study, we investigated the associations between LTPA and OPA and risk of all-cause mortality, recurrent cardiovascular events and incident T2D in patients with a history of CVD.

      Methods

      Study population

      Data were used from the Utrecht Cardiovascular Cohort-Second Manifestations of ARTerial Disease (UCC-SMART) Study, an ongoing single-centre prospective cohort comprising patients aged 18–79 years with cardiovascular risk factors or established CVD.19 For the current study, data were used from 7058 patients, included in the cohort between January 2002 and December 2019 with established coronary artery disease, peripheral artery disease (PAD) or cerebrovascular disease (CeVD) at inclusion in the cohort. Analyses on T2D incidence were limited to participants without T2D at baseline (N=5765, online supplemental figure 1).

      Supplemental material

      Baseline measurements

      Upon inclusion in the UCC-SMART cohort, participants completed a standardised questionnaire on medical history, cardiovascular risk factors and medication use. Patients underwent physical examination, and laboratory measurements were performed.

      LTPA and OPA were self-reported in the baseline questionnaire. LTPA was defined as activity from sports, walking, cycling and gardening and was assessed using validated ranking physical activity questionnaire20 with an additional question on sport activity. LTPA was expressed as metabolic equivalent of task hours per week (METh/wk). METh/wk combines intensity and duration of the activity by multiplying the reported weekly hours of physical activity with activity-specific MET intensity obtained from the Compendium of Physical Activity.21 To exemplify: a participant who walks (estimated at 3.5 MET) 2 hours per week would perform (2×3.5)=7.0 METh/wk. OPA was quantified using a question with four intensity levels that assessed the physical activity intensity during participants’ last active employment. These four levels were: predominantly sedentary work, standing work, manual work and heavy manual work.

      Clinical outcomes

      Participants were sent biannual follow-up questionnaires on vital status and the occurrence of cardiovascular events. When participants reported an event, additional information was obtained from the treating physician or hospital. The endpoint classification was made independently by three physicians in accordance with previously published definitions.19

      The primary outcomes were all-cause mortality, recurrent cardiovascular events and incident T2D. Recurrent cardiovascular events were a composite of non-fatal myocardial infarction (MI), non-fatal stroke and cardiovascular mortality. The individual components of the vascular composite endpoint were assessed as secondary endpoints.

      Data analyses

      Baseline characteristics were reported stratified for quarters of the LTPA distribution and OPA categories. Categorical variables were presented as frequencies with percentages and continuous variables as means with SD or medians with IQR. Multivariable-adjusted Cox models with time-on-study as time scale were used to estimate the associations for LTPA and OPA. Patients who were lost to follow-up (N=446, 6%) were censored on the last day their status was known. The proportional hazard assumption was checked by visual inspection of Schoenfeld residuals. Model 1 adjusted for age and sex. Model 2 adjusted for model 1, smoking status, number of pack years and alcohol use. Model 3, the main model, additionally adjusted for education level and employment status. In model 4, further adjustments were made for variables that could be either confounders or intermediates: T2D, body mass index (BMI), systolic blood pressure and low-density lipoprotein cholesterol (LDL-C). The models for LTPA and OPA were not mutually adjusted for each other. The associations of LTPA as a continuous variable were assessed using restricted cubic splines with three knots in Cox models adjusted for the covariates in model 3.

      Interplay between LTPA and OPA was assessed by comparing the effect of different combinations of LTPA and OPA against a common reference (ie, LTPA quarter 1 and sedentary OPA). Sex, age, education, employment status, type of pre-existing CVD, presence of metabolic syndrome, BMI, systolic blood pressure and LDL-C levels were assessed as potential effect modifiers. Effect modification was tested by introducing multiplicative interaction terms into the Cox models. Bonferroni correction was used to account for multiple testing. Subgroup analyses based on strata of sex, smoking status and employment status were run. To assess the impact of reverse causation, the primary analyses were repeated with removal of the first 1, 3 and 5 years of follow-up.

      Missing data on LTPA (1%), OPA (7%), education (33%), metabolic syndrome (1%), smoking status (1%), alcohol consumption (1%) and LDL-C levels (7%) were imputed with single imputation using predictive mean matching. A complete case analysis was run to assess the robustness of the imputation. All statistical analyses were performed using R statistical software, V.4.0.3 (R Foundation for Statistical Computing, Vienna, Austria).

      Results

      Figure 1 summarises the study design and key findings.

      Figure 1
      Figure 1

      Central figure of study design and key findings. CVD, cardiovascular disease; METh/wk, metabolic equivalent of task hours per week; T2D, type 2 diabetes; UCC-SMART, Utrecht Cardiovascular Cohort-Second Manifestations of ARTerial disease.

      Baseline characteristics

      Patients with higher levels of LTPA were more frequently men (top vs lowest LTPA quarter, 77% vs 69%), more often had a history of coronary artery disease (68% vs 60%), were less likely to smoke (24% vs 35%) and reported more physically demanding OPA (35% (heavy) manual OPA vs 28%, table 1). Patients with more physically demanding OPA had lower education levels, were more frequently smokers and had a higher BMI (online supplemental table 1). Participants with active employment were younger than those who were not actively employed, but otherwise had similar distributions of baseline characteristics.

      View this table:
      Table 1

      Baseline characteristics stratified for LTPA

      Association between LTPA and risk of all-cause mortality, recurrent cardiovascular events and incident T2D

      Over a follow-up of 8.6 years (IQR: 4.6–12.5 years), 1254 patients (18%) died and 1088 patients (15%) experienced a recurrent cardiovascular event. Incident T2D was diagnosed in 447 participants (8%). For all-cause mortality and recurrent cardiovascular events, LTPA showed a reverse J-shaped association and the association with incident T2D risk was approximately linear (figure 2). Compared with the lowest LTPA quarter, participants in the highest quarter had a lower risk of all-cause mortality (HR 0.63, 95% CI 0.54 to 0.74), recurrent cardiovascular events (HR 0.72, 95% CI 0.60 to 0.84) and incident T2D (HR 0.72, 95% CI 0.55 to 0.93, table 2). The decreased risk of recurrent cardiovascular events was driven by cardiovascular mortality (HR 0.54, 95% CI 0.42 to 0.69, LTPA Q4 vs Q1) and non-fatal stroke (HR 0.87, 95% CI 0.64 to 1.17, online supplemental figure 2/online supplemental table 2). LTPA was associated with a slightly increased risk of non-fatal MI (HR 1.06 95% CI 0.91 to 1.24, online supplemental figure 2/online supplemental table 2).

      View this table:
      Table 2

      Association between leisure-time physical activity and all-cause mortality, recurrent cardiovascular events and incident type 2 diabetes

      Figure 2
      Figure 2

      Continuous association between leisure-time physical activity and risk of all-cause mortality, recurrent cardiovascular events and incident type 2 diabetes. Associations between continuous leisure-time physical activity and all-cause mortality (A), recurrent vascular events (B) and incident type 2 diabetes (C). HRs are adjusted for age, sex, smoking status, pack years, alcohol consumption, education and current employment (model 3). The histograms inside the figures represent the number of study participants that achieved a certain leisure-time physical activity level. METh/wk, metabolic equivalent of task hours per week.

      Association between OPA and risk of all-cause mortality, recurrent cardiovascular events and incident T2D

      For all-cause mortality and recurrent cardiovascular events, there was an increased risk in the groups with higher OPA (HR 1.08, 95% CI 0.86 to 1.35 and HR 1.15, 95% CI 0.91 to 1.45, respectively, heavy manual vs sedentary, table 3). Standing work conferred an increased risk of all-cause mortality (HR 1.14, 95% CI 0.99 to 1.31 vs sedentary) and manual work conferred an increased risk of recurrent cardiovascular events (HR 1.10, 95% CI 0.94 to 1.28 vs sedentary). Heavy manual work was associated with a higher non-fatal stroke risk (HR 1.66, 95% CI 1.10 to 2.50 vs sedentary, online supplemental table 2). OPA was not associated with incident T2D (table 3).

      View this table:
      Table 3

      Association between occupational physical activity and all-cause mortality, recurrent cardiovascular events and incident type 2 diabetes

      Effect modification

      Figure 3 shows the interaction between LTPA and OPA. For all-cause mortality and T2D, higher levels of LTPA were associated with a lower risk regardless of OPA level. For recurrent cardiovascular events, the protective association of LTPA was not present in participants with (heavy) manual work. When looking at the different components of recurrent vascular events, this effect modification of (heavy) manual OPA on LTPA was most pronounced in the associations with non-fatal MI and stroke (online supplemental figure 3).

      Figure 3
      Figure 3

      Interaction between leisure-time (LTPA) and occupational physical activity (OPA) on the risk of all-cause mortality recurrent vascular events and incident type 2 diabetes. HRs assessing the interaction between LTPA and OPA level in the association with all-cause mortality, recurrent cardiovascular events and incident type 2 diabetes. These figures show the HRs for each combination of LTPA and OPA level with the least active (quarter 1 LTPA and sedentary OPA) as reference category. Models were adjusted for age, sex, smoking, pack years, alcohol consumption, education and current employment (model 3). Numerical values for the presented HRs are included in online supplemental table 3.

      Figure 4 shows the associations between LTPA and OPA across strata of potential effect modifiers. LTPA was strongly associated with risk reductions in patients with multiple CVD types and PAD, but had smaller effects in patients with a history of coronary disease, CeVD or abdominal aortic aneurysm. Across age strata, the association between LTPA and recurrent vascular events was stronger for patients aged 60 years or older.

      Figure 4
      Figure 4

      Potential effect modifiers in the association between leisure-time (LTPA) and occupational physical activity (OPA) and clinical endpoints. (A) Effect modification in association with all-cause mortality; (B) effect modification in association with recurrent cardiovascular events. Association between the highest versus lowest quarter of LTPA and heavy manual OPA versus sedentary OPA and all-cause mortality and recurrent cardiovascular events, stratified for potential effect modifiers. HRs are adjusted for age, sex, smoking status, pack years, alcohol consumption, education and active employment (model 3). After Bonferroni correction for multiple testing, a p value of <0.001 (<0.05/36 tests) was considered statistically significant. AAA, abdominal aortic aneurysm; BMI, body mass index; CAD, coronary artery disease; CeVD, cerebrovascular disease; CVD, cardiovascular disease; LDL, low-density lipoprotein; MetS, metabolic syndrome; PAD, peripheral artery disease; persyr, person-years.

      The associations of OPA with all-cause mortality and recurrent events differed across sex strata, with a protective association of heavy manual OPA in women and a detrimental effect in men (figure 4A,B). Similarly, the associations differed across strata of pre-existing CVD type: protective associations were found for people with PAD and harmful associations were found for people with CeVD. For patients with multiple CVD manifestations, higher OPA was associated with reduced risk of recurrent cardiovascular events (HR 0.58, 95% CI 0.33 to 1.00), while there was no association for patients with a single CVD type. The associations for OPA were stronger for people with a higher education level, with a recurrent events HR of 1.48 (95% CI 0.52 to 4.23) for heavy manual work in highly educated participants compared with an HR of 1.10 (95% CI 0.88 to 1.88) in participants with lower education.

      Subgroup and sensitivity analyses

      In never-smokers, higher LTPA was associated with a lower risk of all-cause mortality and recurrent cardiovascular events compared with the full population, with HR 0.56 (95% CI 0.38 to 0.83) for all-cause mortality and HR 0.45 (95% CI 0.29 to 0.71) for recurrent vascular events (online supplemental table 4). Conversely, OPA seemed to be associated with increased risk of the primary outcomes in never-smokers (eg, incident T2D HR 1.87, 95% CI 1.04 to 3.37 for manual vs sedentary OPA).

      In actively employed participants (N=3478), OPA was more strongly associated with detrimental health effects compared with unemployed or retired participants, especially for recurrent vascular events (HR 1.30, 95% CI 1.01 to 1.67 for heavy manual vs sedentary, online supplemental table 5). The harmful health effects of OPA were more pronounced in men (online supplemental table 6A–D).

      To address potential reverse causality, sensitivity analyses were performed excluding participants who experienced an outcome within 1, 3 or 5 years after inclusion and the results were similar in size and direction to main analysis (online supplemental figure 4). A complete case analysis resulted in associations that were similar in size and direction to the main analysis (data not shown).

      Discussion

      In patients with established CVD, higher levels of LTPA were associated with a lower risk of all-cause mortality, recurrent cardiovascular events and incident T2D. In contrast, OPA, especially standing and manual work, was associated with an increased risk of all-cause mortality and recurrent cardiovascular events, notably in men, actively employed participants, patients with a history of CeVD and non-smokers. Furthermore, the beneficial effects of LTPA were attenuated in patients with (heavy) manual work. These findings suggest that the physical activity paradox also manifests in patients with established CVD.

      The health benefits of increasing LTPA are widely accepted in healthy populations and supported by multiple prospective cohort studies.8–10 In patients with established CVD, studies show that people with the highest LTPA level have up to 50% lower risk of all-cause mortality and 35% lower risk of recurrent CVD events, which is in line with the findings in our study.17 18 In the present study, the association between LTPA and cardiovascular and mortality risk had a reverse J-shape, meaning that a level of LTPA exists beyond which additional activity no longer confers further risk reduction. This finding is in line with previous studies in apparently healthy populations8 and with findings in two cohorts of patients with CVD.17 18 Potential explanations for the plateauing and even reversal of the beneficial effects of LTPA at higher levels include atherosclerotic plaque rupture during vigorous exercise or triggering of arrhythmias in scarred myocardial tissue.22 23

      Interestingly, LTPA was protective of cardiovascular mortality and non-fatal stroke but was associated with an increase in non-fatal MI risk. A potential explanation for these contrasting associations is that LTPA does not reduce the number of events, but prevents events from being fatal by limiting the ischaemic damage incurred to heart muscle. Mechanisms for this process include improved blood flow, vasodilation and angiogenesis in coronary arteries.24 25 These adaptations could reduce infarct size and infarction-reperfusion injury after a recurrent cardiovascular event.

      The associations of LTPA and OPA with T2D have not extensively been studied in CVD populations, but in apparently healthy populations, a linear association with LTPA was observed.10 Potential explanations for the protective effect of LTPA on T2D include weight loss and increased insulin sensitivity through upregulation of GLUT4 transporters in skeletal muscles.10 26 In the present study, OPA was not associated with T2D risk. Possible explanations for this lack of effect include that OPA is associated with other lifestyle factors that increase the risk of T2D (eg, unhealthy diet) or that the low-intensity, repetitive character of OPA puts less strain on skeletal muscles and therefore does not result in upregulation of GLUT4.

      In apparently healthy populations, higher OPA levels have been associated with up to 50% increased risk of mortality and CVD.12 In the present study, higher OPA levels were associated with risk increases of approximately 10%, which is in line with previous evidence from exploratory analyses in CVD subgroups.16 A possible explanation for this difference in effect size could be that UCC-SMART participants with CVD were around retirement age, while OPA conferred stronger harmful effects in a subgroup of actively employed participants. Furthermore, the results could have been affected by index event bias.

      Although standing work is commonly thought of as health promoting, this idea might not hold for patients with established CVD.27 Our results showed that standing OPA was associated with increased risk of all-cause and cardiovascular mortality and non-fatal stroke. The haemodynamic effects of prolonged standing may lead to blood pooling in the extremities, increased pulse pressure and vascular turbulence, ultimately increasing risk of cardiovascular, specifically cerebrovascular, events.15

      An explanation for the contrasting health effects of LTPA and OPA should be sought in the differing characteristics of the physical activity types.28 LTPA usually has higher intensity and shorter duration, while OPA requires low-intensity repetitive movements with short recovery times. Therefore, it has been hypothesised that OPA does not lead to the cardiovascular benefits and improved cardiorespiratory fitness that can be achieved with LTPA and instead has unhealthy effects, such as increased 24-hour heart rate, systolic blood pressure and systemic inflammation.28

      Another explanation for the finding that OPA does not improve health outcomes might be residual confounding. Manual work is associated with heavier smoking habits and unhealthy diet. Furthermore, people with manual work have has a higher chance of exposure to toxic environmental factors and more frequently do shift work which is independently associated with increased CVD risk.29 In the current analyses, attempts were made to account for socioeconomic status by adjusting for education level, and the estimated HR decreased slightly toward the null. In studies with more extensive adjustment for socioeconomic factors, the detrimental health effects of OPA were still upheld.12 In never-smokers, the detrimental associations of OPA were also found, indicating that residual confounding from smoking status did not bias the main findings. Ultimately, it is difficult to disentangle the effect of OPA itself from the effects of other (lifestyle) factors that often accompany it. Further research is needed to better understand the effects of physically demanding work so specific OPA recommendations can be implemented in guidelines.

      Strengths of our study include its size, prospective design, comprehensive data collection and low rate of loss to follow-up. Study limitations include that OPA level was assessed at baseline only, while the majority of the study population was no longer actively employed at that time. This may have diluted the overall effect estimates for OPA, as a sensitivity analysis in actively employed patients yielded stronger associations. Moreover, the physical activity questionnaire was only validated for ranking participants from lowest to highest LTPA level and, therefore, it was impossible to estimate an optimal LTPA level. Furthermore, LTPA and OPA were based on self-reporting, which may lead to optimistic estimates due to social desirability bias. There is, however, no reason to assume the extent of over-reporting differs between low and high levels of LTPA, which means that ranking of individuals will remain unaffected. OPA estimates may have been biased by a healthy workers effect, an important form of selection bias in occupational epidemiology research, because unhealthy people are more likely to switch to less physically demanding occupations.30 As a result, the associations for the more physically demanding OPA categories could have been biased towards the null.

      In conclusion, in patients with established CVD, higher LTPA was associated with a lower risk of all-cause mortality, recurrent cardiovascular events and incident T2D, but this relationship was not observed for higher OPA levels. These findings support the existence of a physical activity paradox in patients with established CVD, because they show that while LTPA is beneficial, physically demanding OPA may have harmful effects. Healthcare providers should be aware of these potentially harmful effects of OPA, and OPA should therefore not be regarded as a substitute for LTPA.

      Data availability statement

      Data are available upon reasonable request. The data that support the findings of this study are available from the corresponding author upon reasonable request.

      Ethics statements

      Patient consent for publication

      Ethics approval

      This study involves human participants and was approved by the local Medical Research Ethics Committee-University Medical Center Utrecht (reference number: 22-088). Participants gave informed consent to participate in the study before taking part.

      Acknowledgments

      We gratefully acknowledge the contribution of the research nurses; R van Petersen (data manager); Angela Vandersteen (study manager) and the members of the Utrecht Cardiovascular Cohort-Second Manifestations of ARTerial disease Study group (UCC-SMART Study group): F W Asselbergs and H M Nathoe, Department of Cardiology; G J de Borst, Department of Vascular Surgery; M L Bots and M I Geerlings, Julius Center for Health Sciences and Primary Care; M H Emmelot, Department of Geriatrics; P A de Jong and T Leiner, Department of Radiology; A T Lely, Department of Obstetrics & Gynecology; N P van der Kaaij, Department of Cardiothoracic Surgery; L J Kappelle and Y M Ruigrok, Department of Neurology; M C Verhaar, Department of Nephrology; F L J Visseren (chair) and J Westerink, Department of Vascular Medicine, University Medical Center Utrecht and Utrecht University.

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      Footnotes

      • Collaborators On behalf of the UCC-SMART Study group.

      • Contributors NEB was responsible for designing the work, performing data analyses, interpreting the results and drafting the manuscript. YR, MJMC, GJdB and AMM were responsible for revising the manuscript. CK was responsible for designing the work, interpreting the results and revising the manuscript. FLJV was responsible for designing the work, interpreting the results and revising the manuscript, and is the manuscript’s guarantor.

      • Funding The UCC-SMART Study was financially supported by a grant from the University Medical Center Utrecht, the Netherlands. The research presented in this paper was supported by a grant from the Regio Deal Foodvalley (162135).

      • Competing interests None declared.

      • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

      • Provenance and peer review Not commissioned; externally peer reviewed.

      • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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